LATS1

肝转移是结直肠癌(CRC)患者死亡的主要原因。新出现的证据表明，环状RNA (circRNA)在癌症进展中起着关键作用。然而，其在结直肠癌肝转移中的作用在很大程度上仍然未知。2023年12月13日，中山大学潘志忠、林俊忠及周驰共同通讯在Molecular Cancer（IF=37）在线发表题为“A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis”的研究论文，该研究证明，由m6 A修饰的环状RNA驱动的正反馈回路促进结直肠癌肝转移。Circ-YAP在伴有肝转移的结直肠癌中显著上调，与预后不良相关。Circ-YAP促进CRC细胞在体外的迁移和侵袭，并促进患者源性异种移植(PDX)模型体内的肝转移。从机制上讲，circ-YAP编码了一种含有220个氨基酸的新型截断蛋白，称为YAP-220aa，该蛋白与LATS1竞争性结合，导致YAP去磷酸化和核易位，从而激活一系列促进转移的基因。重要的是，N6-甲基腺苷(m6 A)修饰协调了circ-YAP翻译的有效起始，需要m6 A“读取器”YTHDF3和eIF4G2翻译起始复合物。有趣的是，circ-YAP被YAP/TEAD复合物转录增强，从而形成一个正调控前馈回路。总之，该研究揭示了circ-YAP编码的一个以前未被表征的癌蛋白，这意味着一个有希望的结直肠癌肝转移患者的生物标志物和治疗靶点。结直肠癌(Colorectal cancer, CRC)是消化道最常见的恶性肿瘤之一，其发病率和死亡率在所有恶性肿瘤中分别排名第三和第二位。肿瘤转移是结直肠癌患者死亡的主要原因。临床上约有45-60%的结直肠癌患者存在肝转移，90%以上的肝转移不能初步切除。未经手术治疗的结直肠癌肝转移患者中位生存时间仅为6.9个月，5年生存率不足5%。因此，破解结直肠癌肝转移机制，发现预防和干预转移的新治疗靶点，提高患者生存率具有重要的临床意义。环状RNA (Circular RNA, circRNA)是一类特殊的内源性RNA分子，具有共价闭环结构，没有传统的5′端“帽状结构”和3′端聚A尾部。一些circRNA被确定为预测疾病进展和预后的可用生物标志物。最近的一些证据表明circRNA能够被翻译成功能性肽。此外，circRNAs编码的截断蛋白如E-Cad-254aa和ARHGAP35-1289aa分别被报道在胶质瘤和肝细胞癌中发挥关键作用。由于从头到尾的形状，circRNA以帽独立的方式编码蛋白质，由内部核糖体进入位点(IRES)或m6 A修饰驱动。m6 A是真核RNA中最丰富的内部修饰，具有动态可逆性，由m6 A写入器(METTL3/14和WTAP)催化，由m6 A“擦除器”(FTO和ALKBH5)去除，由m6 A读取器(YTHDF1/2/3和ythdc2 /2)识别。迄今为止，只有少数这些隐藏在环状RNAs中的小内源性蛋白被表征，绝大多数的功能相关性尚未被发现。机理模式图（图源自Molecular Cancer ）该研究发现circRNA circ-YAP是CRC肝转移的驱动因素。Circ-YAP包含一个220-aa的开放阅读框(ORF)，并以m6 A依赖的方式编码一种新的YAP蛋白异构体，称为YAP-220aa。此外，还发现YAP220aa通过阻止LATS1介导的YAP磷酸化和细胞质保留来激活YAP信号。该研究揭示了circ-YAP编码的一个以前未被表征的癌蛋白，这意味着一个有希望的结直肠癌肝转移患者的生物标志物和治疗靶点。参考文献：Zeng K, Peng J, Xing Y, Zhang L, Zeng P, Li W, Zhang W, Pan Z, Zhou C, Lin J. A positive feedback circuit driven by m6A-modified circular RNA facilitates colorectal cancer liver metastasis. Mol Cancer. 2023 Dec 13;22(1):202. doi: 10.1186/s12943-023-01848-1. PMID: 38087322; PMCID: PMC10717141.责编|探索君排版|探索君文章来源|“iNature”End往期精选围观王晓红教授团队：绘制单次冷冻囊胚移植成功的女性植入期外周血microRNA动态表达谱，开拓领域创新研究热文维生素B12在细胞重编程与组织再生中发挥关键作用！热文不孕症治疗新方向！又一导致女性不孕的关键因素被发现热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文一项最新发现或可用于阿尔茨海默病药物开发点击“阅读原文”，了解更多~

近段时间，来自浙江大学的一个研究团队探索了circRNA在膀胱癌中的作用机制，以进一步了解膀胱癌的发生与发展进程。 膀胱癌（BCa）是全球第四大最常见的恶性肿瘤，也是中国最常见的泌尿系统癌症，其预后较差。CircRNA 是一种深奥神秘的长非编码 RNA。大多数 circRNA 由现有蛋白质编码基因的外显子通过非固定的反向剪接组成。由于其共价环结构，circRNA 可以耐受外切酶的降解，比线性 RNA 更为稳定。新近有文献报道，circRNAs 可调控多种人类疾病（尤其是癌症）的发生和发展。迄今为止，已有研究阐明，circRNAs 可作为 microRNA 的诱饵以调节特定蛋白质的表达水平，并作为支架通过共定位加速蛋白质之间的相互作用。前有研究表明，circRNA 参与了膀胱癌的进展。因此，深入研究 circRNAs 对膀胱癌肿瘤发生和发展的调控作用意义重大。 近段时间，来自浙江大学的一个研究团队探索了circRNA在膀胱癌中的作用机制，以进一步了解膀胱癌的发生与发展进程。 研究人员运用RNA 免疫沉淀（RIP）和 circRNA 测序方法，circXRN2 是其研究对象。通过过表达 circXRN2 和敲除 TAZ/YAP 进一步验证了其在 T24 和 TCCSUP 细胞中的生物学功能。再通过免疫沉淀和共沉淀来阐明circXRN2和LATS1之间的相互作用，并海马代谢分析仪用于测定糖酵解率。利用靶标下裂解和标记（CUT&Tag）以及染色质免疫沉淀（ChIP）来确保 H3K18 乳化在 LCN2 转录活性中的调控作用。 研究结果提示circXRN2 在膀胱癌组织和细胞系中异常下调。CircXRN2 在体外和体内都能抑制肿瘤细胞的增殖和迁移。此外，circXRN2 还是糖酵解和乳酸生成的负调控因子。从机理上讲，circXRN2 通过与 SPOP 降解子结合防止 LATS1 被 SPOP 介导的降解，然后激活 Hippo 信号通路发挥各种生物学功能。CircXRN2-Hippo 通路调控轴通过抑制 H3K18 乳化和 LCN2 在人类膀胱癌中的表达，从而进一步调节肿瘤的进展。 通过qRT-PCR在不同细胞系中验证与LATS1结合的circRNA 免疫荧光检测TAZ/YAP在不同丰度circXRN2细胞系中的定位。 在膀胱癌中，CircXRN2通过激活Hippo信号通路抑制由H3K18乳化驱动的肿瘤进展。我们的研究结果指出了新的治疗靶点，并为人类膀胱癌的临床干预提供了有前景的策略。 原始出处：Xie B, Lin J, et al. CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol Cancer. 2023 Sep 8;22(1):151. doi: 10.1186/s12943-023-01856-1. PMID: 37684641; PMCID: PMC10486081.

An international team of researchers has demonstrated that a combination of inhibitors may suppress tumor growth and prevent relapse in patients with certain cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma. Their findings support the future development of innovative therapeutic approaches targeting these cancers. An international team of researchers has demonstrated that a combination of inhibitors may suppress tumor growth and prevent relapse in patients with certain cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma. Their findings support the future development of innovative therapeutic approaches targeting these cancers. The team's work is published in the journal Oncogene on August 17, 2023. Scientists know that in humans and other mammals, the Hippo signaling pathway plays a key role in the rapid increase of cells that occurs with cancers in the body. Yes-associated protein 1, or YAP, is a protein that is critical in regulating the progression of tumor growth, and it plays an important role in the beginning and spread of a variety of cancers. When the Hippo pathway is dysregulated, it triggers the activation of YAP and this contributes to head and neck squamous cell carcinoma. Both the Hippo pathway and YAP have attracted attention as signaling pathways that regulate cancer cell characteristics. Epidermal growth factor receptor, or EGFR, is a protein on cells that contributes to their growth. When a mutation occurs in the gene for EGFR, it can grow too much, leading to cancer. EGFR is frequently amplified and highly overexpressed in head and neck squamous cell carcinoma, and mutated and activated in lung adenocarcinoma. So the EGFR inhibitor, a drug that blocks the cancer's growth, is used as a targeted therapy in fighting these cancers. In earlier work, the research team clarified the mechanism by which EGFR activates YAP through the Hippo pathway. However, EGFR-targeted monotherapy has shown a low response rate. Based on this evidence, researchers believe that EGFR inhibitors may temporarily inactivate YAP, but when YAP is re-activated, it increases resistance to the EGFR inhibitors used to fight the cancer. Scientists do not yet fully understand how the YAP is re-activated. The team focused their current study on AXL, a receptor-type tyrosine kinase. They set out to clarify the mechanism that causes the cancer cells' resistance to EGFR inhibitors, specifically focusing on the novel regulatory mechanism of YAP by AXL. Receptor-type tyrosine kinases like AXL play an important role in cell processes. When it is working properly, AXL is mainly expressed in immune cells, and does the work of removing dead cells and controlling the duration of immune responses. But when AXL becomes dysregulated, they can contribute to cancers, including lung adenocarcinoma, acute leukemia, and head and neck squamous cell carcinoma. The team used comprehensive transcriptional analysis and in vitro experiments in their study. With this research, the team clarified that AXL stimulates YAP through a novel mechanism when AXL combines with EGFR. This combination activates YAP via the EGFR-LATS1/2 axis. LATS1/2, or large tumor suppressor kinases, are important members of the Hippo pathway. The team determined that the combination of AXL and EGFR inhibitors working together inactivates YAP and suppresses the viability of head and neck squamous cell carcinoma and lung adenocarcinoma cells. "The combination therapy targeting both EGFR and AXL or YAP simultaneously may effectively suppress tumor growth and prevent resistance and relapse in patients with EGFR-altered cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma," said Toshinori Ando, assistant professor at the Center of Clinical Oral Examination, Hiroshima University Hospital. Looking ahead, the team plans to try to generate effective drugs that can target EGFR, AXL, and YAP. "We think that intrinsic YAP activation or acquired re-activation after EGFR-targeted therapy in head and neck squamous cell carcinoma and lung adenocarcinoma has not been clarified yet. We will continue the research," said J. Silvio Gutkind, distinguished professor, Department of Pharmacology, University of California, San Diego.